Embolization device for vessel cavity in vivo

ABSTRACT

An embolization device which is placed at a definite position in a vessel cavity in vivo to embolize the vessel cavity. More specifically speaking, an embolization device to be used for plugging a blood vessel or a aneurysm formed in a blood vessel. After being placed in a vessel cavity in vivo, this embolization device promotes not only thrombosis but also organization over the surrounding area, thereby exerting an excellent embolization effect on the vessel cavity. Namely, an embolization device for plugging a vessel cavity in vivo characterized by having biological response modifiers (BRM) which can promote organization and exert an enhanced embolization effect after being placed in a vessel cavity in vivo.

TECHNICAL FIELD

The present invention relates to an embolization device which is placedat a predetermined position in a vessel cavity in vivo to embolize thevessel cavity. More particularly, the invention relates to anembolization device which embolizes a blood vessel or a aneurysm formedin a blood vessel.

BACKGROUND ART

It is known that cerebrovascular diseases are broadly classified intohemorrhagic lesions, such as subarachnoid hemorrhage and intracerebralhemorrhage, and obstructive lesions caused by atheromatous clots or thelike, and that cerebrovascular diseases rapidly develop and have seriousprognoses. Above all, subarachnoid hemorrhage is a serious disease witha mortality rate of about 30% within 48 hours of onset. Furthermore, thefrequency of rebleeding within two weeks after subarachnoid hemorrhageis 20% to 30%, and in the case of rebleeding, the mortality rate isextremely high at 70% to 90%.

Rupture of cerebral aneurysms, such as a cerebral aneurysm 1 (refer toFIG. 1), is the cause of 80% of all subarachnoid hemorrhages. Rupturedaneurysms are treated surgically to prevent rebleeding, and clipping isthe most radical treatment. In the clipping treatment, a craniotomy isperformed and then a neck (base) 2 of the cerebral aneurysm (refer toFIG. 1) is clipped to prevent rerupture. However, in the case of highseverity, such as deep coma or unstable blood pressure, it is difficultto perform such clipping treatment. Consequently, about only half ofpatients with subarachnoid hemorrhage caused by rupture of cerebralaneurysms are treated by clipping. Furthermore, clipping is an invasivetreatment requiring a craniotomy, and infection associated, with thecraniotomy is a problem. Moreover, since direct surgery is performed inthe clipping treatment, depending on the site of the cerebral aneurysm,there may be a case in which it is difficult to perform a surgicalprocedure, which is also a problem.

Recently, as a less invasive treatment, vascular embolization, in which,as described in Japanese Patent No. 2880070, an embolization device ispercutaneously placed in a cerebral aneurysm to prevent rerupture, hasbeen receiving attention. In the vascular embolization, the embolizationdevice placed in the cerebral aneurysm serves as a physical obstacle toblood flow and thrombi are formed around the embolization device, andthus it is possible to prevent the rerupture of the cerebral aneurysm.As the embolization device to be placed in the cerebral aneurysm, anembolization device comprising a metal coil (hereinafter referred to asan “embolization coil”) has been commonly used. Consequently, vascularembolization using an embolization coil is often called “coilembolization”. Such an embolization coil is percutaneously guidedthrough a suitable catheter to a cerebral aneurysm and then placed inthe cerebral aneurysm by a push-out device detachably connected to theend of the embolization coil. Therefore, the coil embolization can beapplied in cases of high severity to which clipping treatment is notapplicable and to elderly people.

The coil embolization is performed using X-ray fluoroscopy because it isa percutaneous treatment as described above. In order to achievevisibility by X-ray fluoroscopy, the embolization coil is generallycomposed of platinum or a platinum alloy.

However, coil embolization is not applicable to the treatment of allruptured cerebral aneurysms because of its specific problems. Forexample, when coil embolization is used in a cerebral aneurysm with alarge diameter, it is difficult to completely embolize the aneurysm, andcompaction of the indwelling embolization coil (coil compaction) easilyoccurs after treatment, resulting in a high possibility of rebleeding.Furthermore, in the case of a cerebral aneurysm with a wide neck 2(refer to FIG. 1), the indwelling embolization coil is easily dislodgedfrom the aneurysm to a parent blood vessel 3 (refer to FIG. 1), and ithas been pointed out that there is a possibility of complications, suchas cerebral infarction, being caused because the thrombi formed on thesurface of the dislodged embolization coil flow to peripheries throughthe bloodstream. Moreover, in the case of a cerebral aneurysm which isformed in a branch of a blood vessel, there is a risk of occlusion inthe branch. As described above, although coil embolization is a lessinvasive treatment, the shape of a cerebral aneurysm for which the coilembolization can be used is limited, and the coil embolization is notyet a technique that is superior to clipping treatment.

Many studies have been conducted using autopsy and animal experimentsregarding the tissue response in cerebral aneurysms treated with coilembolization. As a result, it has been found that if an embolizationcoil is placed in an aneurysm, fibrous tissue is formed by successivecell responses and that the successive cell responses follow the samepattern as that of the wound healing response as shown in Am JNeuroradiol, 1999, 20, 546-548; Neurosurgery, 1998, 43, 1203-1208;Stroke, 1999, 30, 1657-1664; J Neuroradiol, 1999, 26, 7-20; etc.

The wound healing response is believed to include the following fivesuccessive steps. Namely, when a wound is caused, blood coagulation andthrombus formation occur due to the activation, adhesion, andaggregation of platelets. Furthermore, activation of the coagulationsystem and activation of the complement system are initiated. Theseresponses are observed mainly one to two days after the wound hasoccurred, and are generically referred to as a response in thecoagulation/hemostasis phase.

Subsequently, increased blood vessel permeability and vasculardilatation are caused by the actions of histamine, serotonin,prostacyclin, etc. Furthermore, because of PDGF and TGF-β, infiltrationand migration of inflammatory cells, such as neutrophils andmacrophages, are observed, and lymphocytes appear simultaneously.Phagocytosis of macrophages is initiated, and various cytokines (e.g.,PDGF, VEGF, TNF-α, and CSF-1) are secreted from macrophages. Theseresponses are observed mainly one to seven days after the wound hasoccurred, and are generically referred to as a response in theinflammation phase.

Subsequently, proliferation of fibroblasts is initiated by the actionsof cytokines, such as TGF-β and IL-4, derived from macrophages, andsynthesis of extracellular matrix and neovascularization are alsoinitiated. These responses are observed mainly three days to two weeksafter the wound has occurred, and are generically referred to as aresponse in the proliferation phase.

Subsequently, tissue reconstruction is carried out by collagencrosslinking, formation of granulation tissue, contraction of the wound,epithelialization, etc. These responses are observed mainly five days tothree weeks after the wound has occurred, and are generically referredto as a response in the tissue reconstruction phase.

Lastly, cicatrization and involution of the vascular system occur, andthus the wound healing is completed. These responses are observed mainlytwo weeks to two years after the wound has occurred, and are genericallyreferred to as a response in the maturation phase.

Platinum, which is a material mainly constituting the embolization coilscurrently in use, is extremely inactive in vivo, and therefore, fibroustissue formation (organization) does not easily take place in cerebralaneurysms treated with coil embolization. This fact has been pointed outas a limiting factor in the application of coil embolization.

Under such circumstances, prior art techniques have been disclosed topromote thrombus formation around embolization coils.

Namely, in order to enhance thrombus formation on embolization coilshaving various shapes and properties, such as flexibility, techniquesfor attaching fibrous members to the embolization coils are disclosed,for example, in Japanese Examined Patent Application Publication No.7-63508 and Japanese Patent Nos. 2553309, 2682743, 2986409, 3023076,3024071, and 3085655. However, attachment of a fibrous member to anembolization coil gives rise to problems. For example, the fabricationprocess becomes complex. Furthermore, since it is difficult to view thefibrous member by X-ray fluoroscopy, there is a possibility that thefibrous member may be dislodged into a parent blood vessel, resulting incomplications, such as cerebral infarction. Moreover, the coefficient offriction of the surface of the embolization coil is extremely increasedby the attachment of the fibrous member, and operationality duringguiding of the embolization coil through a catheter is decreased.

In other prior art techniques, for example, in Japanese Patent Nos.2620530 and 3016418, inclusion of biocompatible polymers intoembolization coils having a specific shape and properties, such asflexibility, is disclosed. However, the biocompatible polymers disclosedare fibrous materials with thrombus-forming properties, and it isevident that there is a possibility of the same problems occurring asthose described above. Furthermore, in other prior art techniques, forexample, Japanese Patent No. 2908363 and Japanese Unexamined PatentApplication Publication No. 11-76249, helical coils each provided with astrand composed of a biologically active material and axially extendingtherein are disclosed. However, since the strand that can be placed inthe embolization coil has an extremely small diameter, it is difficultto produce such a strand. Furthermore, the flexibility of the entireembolization coil is inevitably decreased because of the placement ofthe strand, and thus there is an unavoidable possibility of causingserious complications, such as perforation of the aneurysm during theplacement of the embolization coil.

In view of the problems described above, it is an object of the presentinvention to readily provide an embolization device which promotes notonly thrombus formation but also organization around the embolizationdevice after it has been placed, thus showing a superior embolizingeffect compared with the conventional embolization devices.

DISCLOSURE OF INVENTION

The present inventors have conducted intensive research in order toovercome the problems described above. As a result, an embolizationdevice for embolizing a vessel cavity in vivo has been invented, theembolization device being characterized in that it includes a biologicalresponse modifier (BRM). Herein, the vessel cavity in vivo can be ablood vessel or a aneurysm formed in a blood vessel.

The BRM is preferably applied by coating to a surface of theembolization device. Furthermore, the BRM is preferably apolysaccharide.

The polysaccharide is preferably chitin, chitosan, or a β(1→3) glucan.The β(1→3) glucan is preferably curdlan.

The β(1→3) glucan may have a branch comprising a (1→6) glucan. Theβ(1→3) glucan having the branch comprising a β(1→6) glucan is preferablylentinan or sizofiran.

In addition, the embolization device is preferably a coil. Morepreferably, the coil comprises a metal wire composed of any one ofplatinum, gold, silver, and tantalum, or an alloy wire containing anyone of platinum, gold, silver, and tantalum in an amount of 80% byweight or more.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic diagram showing a typical shape of a cerebralaneurysm which causes subarachnoid hemorrhage.

FIG. 2 is a sectional view showing an example of an embolization devicein the present invention.

FIG. 3 is a side view showing a state in which a push-out device isconnected to the embolization device of the present invention.

REFERENCE NUMERALS

-   -   1 cerebral aneurysm    -   2 neck    -   3 parent blood vessel    -   4 embolization device    -   5 BRM coating    -   6 coil    -   7 diameter of metal wire    -   8 outer diameter of coil    -   9 connecting member    -   10 connecting means    -   11 tip    -   12 radiopaque distal section    -   13 wire section    -   14 flexible portion    -   15 proximal portion    -   16 terminal area    -   17 outer diameter of secondary coil    -   18 push-out device

BEST MODE FOR CARRYING OUT THE INVENTION

Various embodiments of an embolization device of the present inventionwill be described below in detail.

Biological response modifiers (BRMs), which are proposed by the U.S.National Cancer Institute, refer to substances that modify thebiological response of the host (living body) to tumors, such as cancer,or attempts to use such substances to enhance therapeutic effects.Examples of BMRs include polysaccharides and cytokines, such asinterferons (IFNs), interleukins (ILs), and tumor necrosis factor (TNF).Furthermore, various clinical attempts have been made in which immunityto disease other than cancer, in particular, autoimmune disease, isenhanced by BRMs to restore homeostasis.

The present inventors have examined the wound healing response withreference to the finding that the tissue response in aneurysms treatedwith coil embolization follows the same pattern as that of the woundhealing response. As a result, based on the fact that immunocytes, suchas macrophages, play an important role in various phases in the woundhealing response, an embolization device that is provided with a BRM hasbeen invented.

As described above, examples of the BRM include polysaccharides andcytokines. Since the embolization device of the present invention is adevice placed in the body to embolize a vessel cavity in vivo, theembolization device must be sterilized when it is used. Thesterilization is performed, for example, by autoclave sterilization,ethylene oxide gas sterilization, gamma-ray sterilization, orelectron-beam sterilization. In consideration of the possibility thatcytokines might be modified by heat or the like during sterilization,the BRM is preferably a polysaccharide rather than a cytokine.

Chitin, whose chemical name is poly-N-acetyl-D-glucosamine, is apolysaccharide that constitutes the exoskeleton of crustaceans andinsects, the cell membrane of fungi, etc. Chitosan is produced bydeacetylation of the aminoacetyl group of chitin. It is known that ifchitin or chitosan is allowed to act on damaged tissue, the productionof macrophages is increased, thus increasing the number of positivecells of lysozyme, which is an important factor to promote woundhealing, and the proliferation of fibroblasts is promoted, resulting inan increase in the production of collagen. Furthermore, it has beenshown that chitin or chitosan improves the in vivo antitumor activity(NK activity and LAK activity) of lymphocytes. These are the reasons forthe preferential use of chitin or chitosan as the polysaccharide.

Furthermore, a β(1→3) glucan is also preferably used as thepolysaccharide. A polysaccharide that is a polymer containing only onetype of monosaccharide is referred to as a simple polysaccharide. Theβ(1→3) glucan is a simple polysaccharide that is a polymer of glucoseand is a polysaccharide that is contained in fruit bodies, mycelia, andcultured products of fungi. Many β(1→3) glucans have antitumor activityas BRMs, and are preferable as the polysaccharide. It has been confirmedthat some β(1→3) glucans have a branch comprising a β(1→6) glucan. Suchβ(1→3) glucans are also known to have antitumor activity as BRMs and arepreferable as the polysaccharide. Examples of the β(1→3) glucan includecurdlan and pachymaran. In view of achieving high activity as the BRM,the β(1→3) glucan is preferably curdlan. Examples of the β(1→6) glucanhaving the branch comprising a β(1→6) glucan include lentinan,sizofiran, sclerotan, and scleroglucan. In view of achieving highactivity as the BRM, lentinan or sizofiran is preferred.

Any known method may be employed to apply the BRM to the embolizationdevice. That is, the BRM may be applied to the embolization device bycoating, adsorption, immobilization by chemical bonding, or the like. Inorder to maintain the activity of the BRM in a vessel cavity in vivo andto simplify the production process, the BRM is preferably applied bycoating.

When the BRM is applied to the embolization device by coating, forexample, a method in which coating is performed by spraying a solutionof the BRM on the embolization device (spray method) or a method inwhich coating is performed by dipping the embolization device in asolution of the BRM and then withdrawing the embolization device fromthe solution, (dipping method) may be used. However, when apolysaccharide is used as the BRM, although depending on the molecularweight of the polysaccharide used, the solution of the BRM has arelatively high viscosity, and therefore, a large scale of equipment isrequired in order to use the spray method. Consequently, coating by thedipping method is more preferable.

Furthermore, the embolization device may be subjected to surfacetreatment in order to efficiently apply the BRM to the embolizationdevice. The surface treatment method is not particularly limited. Forexample, a known method, such as coating, ultraviolet irradiation,plasma exposure, treatment with a silane coupling agent, or ionimplantation may be suitably used. When any one of the surface treatmentmethods is performed, it is important that the BRM be allowed tomaintain its activity in a vessel cavity in vivo.

Such surface treatment may be performed after the BRM is applied to theembolization device so that the embolization device is easily guided toa target vessel cavity in vivo. In such a case, the surface treatmentmethod is not particularly limited. For example, a known method, such ascoating, ultraviolet irradiation, plasma exposure, treatment with asilane coupling agent, or ion implantation may be suitably used. Whenany one of the surface treatment methods is performed, it is of courseimportant that the BRM be allowed to maintain its activity in the vesselcavity in vivo.

The embolization device is intended to be used to embolize a vesselcavity in vivo, preferably a blood vessel, and more preferably aaneurysm formed in a blood vessel. In particular, in the case of aaneurysm, occurrence of rupture of the aneurysm during the placement ofthe embolization device is highly likely to lead to a very seriousprognosis. Therefore, the embolization device is preferably a coil. Theembolization device in the form of a coil can be flexibly deformed inthe aneurysm, and the risk of rupture of the aneurysm can besignificantly reduced.

The embolization device is placed percutaneously and in order to safelyand rapidly embolize a vessel cavity in vivo, the embolization isgenerally performed using X-ray fluoroscopy. Consequently, theembolization device is required to be viewed by X-ray fluoroscopy. It isgenerally known that the visibility of a metal material in X-rayfluoroscopy improves as its density increases. Furthermore, inconsideration of the workability into a coil, in vivo toxicity, etc.,preferably, the coil comprises a metal wire composed of any one ofplatinum, gold, silver, and tantalum, or an alloy wire containing anyone of platinum, gold, silver, and tantalum in an amount of 80% byweight or more. In the case of the alloy wire containing any one ofplatinum, gold, silver, and tantalum in an amount of 80% by weight ormore, the type of metal to be added other than platinum, gold, silver,or tantalum is not particularly limited. By using the alloy to which ametal other than platinum, gold, silver, or tantalum is added, thephysical properties of the coil can be desirably controlled. Forexample, by using an alloy of platinum and tungsten, it is possible toenhance the flexibility of the coil. In the platinum-tungsten alloy, theratio of platinum is preferably 80% to 95% by weight, and morepreferably 90% to 95% by weight.

FIG. 2 is a sectional view showing an example of a structure of anembolization device 4 of the present invention. The embolization device4 includes a coil 6, a BRM coating 5 provided on the coil, and a tip 11connected to and fixed on a distal end of the coil. A connecting member9 is fixed on a proximal end of the coil 6 by connecting means 10. Thetip 11 is preferably fabricated so as to have a smooth, spherical shapefrom the standpoint of prevention of injury to a vessel cavity in vivoto be embolized.

The diameter 7 of the metal wire constituting the coil 6 isappropriately determined according to the properties of the vesselcavity in vivo to be embolized. Usually, the diameter 7 is preferablyabout 0.02 to 0.15 mm. The outer diameter 8 of the coil, which isappropriately determined for the same reason, is usually 0.1 to 1.0 mm,and preferably 0.2 to 0.6 mm.

The length of the embolization device 4 is usually 1 to 1,000 mm,preferably 1 to 500 mm, and more preferably 30 to 300 mm. FIG. 2 showsthe embolization device 4 that linearly stretches. The embolizationdevice 4 has such a shape, for example, when the embolization device 4travels through a catheter. When the embolization device 4 is notconstrained by a tube wall of a catheter or the like, the embolizationdevice 4 preferably has a secondary shape in which the coil 6 is woundas shown in FIG. 3. The secondary shape is preferably a coil shape, andthe outer diameter 17 of the secondary coil shape can be appropriatelyselected according to the inner diameter of a vessel cavity in vivo tobe embolized. When the vessel cavity in vivo to be embolized is ananeurysm, the outer diameter 17 is usually 2 to 40 mm, and preferably 2to 20 mm. However, as the secondary shape, various shapes other than thecoil shape may be selected as long as the object of the presentinvention is not impaired.

The properties of the coil 6 constituting the embolization device 4 donot restrict the present invention at all. Namely, a mechanism forimproving the stretching strength (anti-unravel mechanism) may beprovided in the coil 6. Moreover, the coil 6 is allowed to have asecondary coil shape that is suited to a vessel cavity in vivo to beembolized. Examples of the possible shape include a shape in which thedistal portion of the secondary coil shape is curved inward and a shapein which the proximal portion of the secondary coil shape is curvedinward.

FIG. 3 shows an example of a preferred assembly form in which a push-outdevice 18 is connected to the embolization device 4 of the presentinvention. The push-out device 18 shown in FIG. 3 includes a wiresection 13 and a connecting member 9. The proximal portion of therod-shaped connecting member 9 is connected to the distal end of thewire section 13, and the embolization device 4 is connected to thedistal end of the connecting member 9.

In the example of the present invention shown in FIG. 3, the wiresection 13 includes a proximal portion 15 covered with a coating forelectrically insulating the surface thereof and a flexible portion 14connected to the proximal portion 15, and a radiopaque distal section 12is connected to the flexible portion. The connecting member 9 isconnected to the distal end of the radiopaque distal section 12.

The outer diameter of the wire section 13 is preferably 0.1 to 2.0 mm.The length of the wire section 13 is varied according to the distance tothe vessel cavity in vivo, and for example, is set at 0.1 to 1.8 m. Thematerial for each of the proximal portion 15 and the flexible portion 14is preferably a conductive metal material, such as stainless steel. Forthe radiopaque distal section 12, a radiopaque metal material, such asplatinum, gold, silver, or tungsten, can be suitably used.

The coating provided on the proximal portion 15 can be formed using anyof various known resin materials. The method for forming the coating isnot particularly limited, and can be appropriately selected according tothe properties of the resin material to be used. The coating is usuallyformed using a fluorocarbon resin material or a hydrophilic resinmaterial. Use of a fluorocarbon resin enables a decrease in the surfacefriction of the proximal portion 15, which is preferable in view thatthe embolization device 4 can be easily guided to a target vessel cavityin vivo.

A terminal area 16 which is not covered with the coating and in whichthe metal material is exposed is formed on the proximal end of theproximal portion 15. By using any conductive member, such as aconnector, a plug, or a clip, through the terminal area 16, electricpower can be supplied. The length of the terminal area 16 is notparticularly limited and is sufficient at about 1 to 3 cm.

The connecting member 9 may be composed of any material that does notadversely affect the living body and has characteristics in that theembolization device 4 is separated by heating. A polyvinyl alcohol-basedresin which can be melt-cut by heating is suitably used for theconnecting member 9. However, the material for the connecting member 9is not limited to the polyvinyl alcohol-based resin. A material whichhas a property of being deformed by heating, such as a shape-memoryalloy or a shape-memory resin material, can also be used. As the methodfor cutting off the embolization device 4 in the present invention, anyof various methods can be used as long as the object of the presentinvention is not impaired. Examples of such methods include melt-cuttingby various types of heating, melt-cutting by applying current,electrolytic cutting by applying current, and mechanical cutting (suchas separation by operating a wire from outside the body or a methodusing a shape memory alloy).

The size of the connecting member 9 is not particularly limited, and canbe appropriately set according to the sizes of the wire section 13 andthe embolization device 4 to be used.

Each of the wire section 13 and the embolization device 4 is connectedto and fixed on the connecting member 9. The connecting means is notparticularly limited. For example, bonding using an adhesive, welding,or connection by a physical external force (swanging) may be used. Inthe case of bonding using an adhesive, the type of adhesive is notparticularly limited, and any of various known adhesives can be used.

In one of the preferred embodiments, the assembly is guided into avessel cavity in vivo through a given catheter. Specifically, a givencatheter is percutaneously inserted into the living body and the distalend of the catheter is allowed to reach the vessel cavity in which theembolization device 4 is to be placed.

Subsequently, the assembly is inserted into the catheter from theembolization device 4 side. At this stage, the coil 6 constituting theembolization device 4 is moved inside the catheter with the secondarycoil shape being substantially linearly stretched along the catheter.Furthermore, the embolization device 4 is allowed to protrude from theopening of the distal end of the catheter so that the connecting member9 is positioned at the opening of the distal end of the catheter. Theembolization device 4 then restores the secondary coil shape by arestoring force due to elasticity and is placed in the vessel cavity invivo.

After a ground electrode is mounted on an appropriate skin surface ofthe living body, a high-frequency power source unit is connected to theterminal area 16, and a monopolar high-frequency current is supplied tothe wire section 13. As a result, the temperature of the connectingmember 9 connected to the distal end of the wire section 13 is increasedby self-heating due to the high-frequency current, and the connectingmember 9 is melt-cut or deformed. Consequently, the embolization device4 is separated from the wire section 13, and thus the placement in thevessel cavity in vivo is completed.

For example, when a resin material comprising a polyvinyl alcohol-basedcopolymer is used for the connecting member 9, the embolization device 4can be separated by supplying a high-frequency current for an extremelyshort period of time, e.g., within one to three seconds. The short-timeseparation as described above reduces the burden not only on the livingbody to be treated but also on the operator, which is preferable.

Examples and Comparative Example of the present invention will bedescribed in detail below. However, it is to be understood that thepresent invention is not limited to the examples.

EXAMPLE 1

A platinum-tungsten (8%) alloy wire with a wire diameter of 45 μm waswound to form a coil with an outer diameter of 300 μm and a length of 4mm. Using dimethylacetamide (manufactured by Nacalai Tesque, Inc.) as asolvent in which 5% lithium chloride (manufactured by Nacalai Tesque,Inc.) was dissolved; a 0.5% chitin (manufactured by Wako Pure ChemicalIndustries, Ltd.) solution was prepared. After the coil was dipped inthe 0.5% chitin solution for one minute, the coil was dipped in2-propanol (manufactured by Nacalai Tesque, Inc.) serving as a coagulantsolution for 5 minutes to coagulate the chitin solution, and thereby thesurface of the coil was coated with chitin. The solvent was removed bythorough washing with distilled water, followed by drying at 60° C. Anembolization device coated with chitin was thereby obtained.

EXAMPLE 2

Using a 2% acetic acid (manufactured by Wako Pure Chemical Industries,Ltd.) aqueous solution as a solvent, a 2% Chitosan 1000 (manufactured byWako Pure Chemical Industries, Ltd.) solution was prepared. Anembolization device coated with chitosan was obtained as in Example 1except that a 0.2 N sodium hydroxide (manufactured by Nacalai Tesque,Inc.) aqueous solution was used as a coagulant solution.

EXAMPLE 3

Using a 0.2 N sodium hydroxide (manufactured by Nacalai Tesque, Inc.)aqueous solution as a solvent, a 5% curdlan (manufactured by Wako PureChemical Industries, Ltd.) solution was prepared. An embolization devicecoated with curdlan was obtained as in Example 1 except that an aqueoussolution containing 4% acetic acid (manufactured by Wako Pure ChemicalIndustries, Ltd.) and 26% sodium chloride was used as a coagulantsolution.

EXAMPLE 4

Using a 0.5 N sodium hydroxide (manufactured by Nacalai Tesque, Inc.)aqueous solution as a solvent, 0.5% lentinan (manufactured by YamanouchiPharmaceutical Co., Ltd.) solution was prepared. An embolization devicecoated with lentinan was obtained as in Example 1 except that an aqueoussolution containing 4% acetic acid (manufactured by Wako Pure ChemicalIndustries, Ltd.) was used as a coagulant solution.

EXAMPLE 5

A 1.0% sizofiran solution (Sonifilan, manufactured by KakenPharmaceutical Co., Ltd.) was used. An embolization device coated withsizofiran was obtained as in Example 1 except that ethanol (NacalaiTesque, Inc.) was used as a coagulant solution and washing withdistilled water was not performed.

COMPARATIVE EXAMPLE

A coil formed in Example 1 was used as an embolization device.

(Evaluation of Organization Effect in Rat Simulated Aneurysm)

Rats (female Wistar, 6 weeks old, 140 to 160 g) were intraperitoneallyadministered with, in a dose of 5 mg/rat, pentobarbital (manufactured byDainippon Pharmaceutical Co., Ltd., Nembutal injection) to beanesthetized. In each rat, upon confirmation of deep anesthesia, theskin was incised and the left common carotid artery was exposed. Thebranch between the internal carotid artery and the external carotidartery was ligated, and a section 10 mm from the ligated site proximalto the heart was temporarily ligated with Schwartz clips. The bloodvessel 2 mm from the peripheral ligated site proximal to the heart wasincised and one of the embolization devices obtained in Examples andComparative Example was placed in the cut. A site further proximal tothe heart was ligated, and the Schwartz clips were removed. Thereby, asimulated aneurysm in which the embolization device was placed wasformed. After 14 days, the rats were sacrificed and the simulatedaneurysms were extirpated. After formalin fixation and paraffinembedding, circumferential cross sections were cut and hematoxylin-eosin(HE) staining and Elastica-van Gieson (EVG) staining were performed. Theresulting sections were observed using an optical microscope, and theorganization effect was evaluated.

In the HE-stained sections, in all of Examples 1 to 5, formation oflarge amounts of thrombi and connective tissue was observed around theplaced coil and the simulated aneurysm was substantially completelyembolized. In the newly formed tissue, many new blood vessels wereobserved and proliferation of fibroblasts was also observed. In theEVG-stained sections, production of a large amount of collagen fiber,which is believed to be derived from proliferated fibroblasts, wasobserved around the placed coil, and therefore, the inside of thesimulated aneurysm was evaluated to be adequately organized.

In contrast, in Comparative Example, although formation of connectivetissue was observed to a small extent, the inside of the simulatedaneurysm was substantially completely patent. Formation of new bloodvessels, proliferation of fibroblasts, and production of collagen fiberwere hardly observed in the connective tissue, and therefore, the insideof the simulated aneurysm was evaluated to be insufficiently organized.

INDUSTRIAL APPLICABILITY

As described above, in accordance with the present invention, anembolization device which embolizes a vessel cavity in vivo and which isprovided with a biological response modifier (BRM) is readily provided,and it is possible to promote the organization after the embolizationdevice is placed in the vessel cavity in vivo, resulting in asatisfactory embolizing effect.

1. An embolization device for embolizing a vessel cavity in vivo, theembolization device comprising a biological response modifier (BRM). 2.An embolization device for embolizing a blood vessel, the embolizationdevice comprising a BRM.
 3. An embolization device for embolizing aaneurysm formed in a blood vessel, the embolization device comprising aBRM.
 4. The embolization device according to claim 1, wherein the BRM isapplied by coating to a surface of the embolization device.
 5. Theembolization device according to claim 1, wherein a polysaccharide isapplied by coating to a surface of the embolization device.
 6. Theembolization device according to claim 1, wherein chitin is applied bycoating to a surface of the embolization device.
 7. The embolizationdevice according to claim 1, wherein chitosan is applied by coating to asurface of the embolization device.
 8. The embolization device accordingto claim 1, wherein a β(1→3) glucan is applied by coating to a surfaceof the embolization device.
 9. The embolization device according toclaim 1, wherein curdlan is applied by coating to a surface of theembolization device.
 10. The embolization device according to claim 1,wherein a β(1→3) glucan having a branch comprising a β(1→6) glucan isapplied by coating to a 3urface of the embolization device.
 11. Theembolization device according to claim 1, wherein lentinan is applied bycoating to a surface of the embolization device.
 12. The embolizationdevice according to claim 1, wherein sizofiran is applied by coating toa surface of the embolization device.
 13. The embolization deviceaccording to claim 1, wherein the embolization device is a coil.
 14. Theembolization device according to claim 1, wherein the embolizationdevice is a coil comprising a metal wire comprising any one of platinum,gold, silver, and tantalum, or an alloy wire containing any one ofplatinum, gold, silver, and tantalum in an amount of 80% by weight ormore.